The RESET C2 trial aims to introduce organ sparing treatment or watch-and-wait (WW) to patients with localized deficient mismatch repair (dMMR) colon cancer through use of neoadjuvant pembrolizumab. Patients will be divided into four treatment arms based on their surgical and oncologic risks. Each arm provides different intensity neoadjuvant immunotherapy regimens. Patients with complete response at disease restaging procedures will be offered non-operative management, whereas those with non-complete response will proceed to surgery ± adjuvant chemotherapy as standard of care. A WW protocol with regular disease surveillance continues over survivorship. If there is recurrence, surgery and/or appropriate oncologic therapy will be offered determined by multi-disciplinary teams. This is a national, non-randomised, investigator-initiated trial including patients from 13 hospitals across Denmark. The rationale, design, and clinical response metrics are derived from the RESET C study (NCT05662527) showing efficacy, safety and feasibility of neoadjuvant pembrolizumab in this cohort.
Organ preservation in colorectal cancer has been pioneered in rectal cancer populations, where watch-and-wait (WW) strategies emerged from total neoadjuvant therapy. RESET C2 aims to brings this same treatment paradigm to colon cancer (CC). Despite improvements in surgical outcomes for CC over time, the risk of relapse and disproportionate complications in frail patients remain core challenges. Avoidance of surgery to limit these risks is attractive from a safety perspective but WW approaches have not been validated as curative and oncologically safe in a CC population. The subgroup of patients with CC and deficient mismatch repair (dMMR) proteins are ideal candidates for investigation as they demonstrate marked sensitivity to immunotherapy, which has the capacity to induce complete responses in a substantial proportion. The question of how this can be best leveraged for maximum benefit in a real-world setting remains to be answered. In this study, 152 eligible participants will be recruited nationwide across 13 participating sites in Denmark. Following enrolment, clinicians will assign a surgical risk category using a composite of the American society of anaesthesiology (ASA) score and Eastern Cooperative Oncology Group performance status (ECOG). This input is combined with cancer stage data to allocate patients to one of four treatment arms. Depending on allocation, participants will receive between one to three consecutive cycles of up-front 4mg/kg pembrolizumab (max. 400mg) every six weeks. This is followed by a disease re-evaluation step, involving colonoscopy and contrast CT imaging. Colonoscopy is used to determine local disease response, and cross-sectional CT is used to confirm absence of distant disease. Participants with clinical complete response (cCR) will be eligible for WW, and those with non-cCR will be offered additional pembrolizumab before a second/final re-evaluation. Any patients with cCR at the final re-evaluation will be eligible for WW and those with non-cCR will be offered surgery. Quality of life (QoL) and late effects will be captured via patient reported outcome measures (PROMs) which will be distributed after enrolment, during immunotherapy, and at designated timepoints across survivorship. A separate cohort of 250 CC patients who undergo surgery without neoadjuvant treatment will complete identical PROMs and act as a comparator group after surgical treatment. Final analysis will compare QoL and late effects in patients who are allocated to WW (cCR), with those who receive neoadjuvant treatment and proceed to surgery (non-cCR), and finally those who proceed directly to surgery (matched cohort). Across all treatment arms, enrolled patients will be offered multi-disciplinary prehabilitation. These functional, exercise, and nutrition interventions are graded in intensity and dependent on patient frailty and disease-factors. This forms the backbone of standard-of-care nationally for colorectal cancer patients and is implemented across all participating sites.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
152
1 cycle of 4mg/kg (maximum of 400mg) every 6 weeks
2 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks
3 Cycles of Pembrolizumab 4mg/kg (maximum of 400mg) every 6 weeks
An additional 4mg/kg (maximum of 400mg) cycle of pembrolizumab in the case of non-complete response
Zealand University Hospital
Køge, Denmark
Proportion of patients with clinical complete response (cCR)
The proportion of patients achieving a clinical complete response defined as 1) the absence of residual local tumour based on predefined endoscopic criteria and 2) absence of metastatic disease on cross-sectional CT imaging. Pathological examination may be performed to support the local tumour response assessment when endoscopic findings are equivocal. These tissue specimens will be reported as per the Mandard Tumour Regression Grading system with pathologic Complete Response (pCR) defined as Mandard Tumour Regression Grade 1.
Time frame: Periprocedural
Overall Survival (OS)
Time from inclusion to death from any cause
Time frame: Up to 3 years
Disease-free survival (DFS)
Time from inclusion to disease recurrence or death from any cause, whichever occurs first.
Time frame: Up to 3 years
Major patholological response (MPR) in patients undergoing surgery as per Mandard TRG
Proportion of patients with no residual tumour cells (Mandard Tumour Regression Grade 1) or rare residual tumour cells (Mandard Tumour Regression Grade 2) in the histopathological section after surgery.
Time frame: Perioperative
Adverse events related to pembrolizumab as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Adverse events related to pembrolizumab, assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The scale of adverse events ranges from a minimal value of 1 (mild) to a maximum value of 5 (death) with higher values representing worse outcomes.
Time frame: 1 year
Adverse events related to surgery as per Clavien-Dindo (CD) classification
Surgical complications graded according to the Clavien-Dindo (CD) classification system. The scale of complications ranges from a minimal value of 0 (no complications) to a maximum value of 5 (death) with higher values representing worse outcomes.
Time frame: Up to 12 weeks
Adverse events related to endoscopy as per American Society for Gastrointestinal Endoscopy (ASGE) lexicon
Endoscopic complications described according to the American Society for Gastrointestinal Endoscopy (ASGE) Lexicon for adverse events. This requires categorical reporting of timing (pre-procedure, intra-procedure, post-procedure \<14 days, late \>14 days), attribution to procedure (definite, probable, possible, unlikely) and severity grade (mild, moderate, severe, fatal).
Time frame: Periprocedural
Planned or unplanned use of hospital services
Number and type of hospital encounters, including inpatient admissions, intensive care admissions, and outpatient visits, occurring in patients managed with watch-and-wait compared to those undergoing surgery. All hospital services will be recorded and analyzed to compare utilization between management strategies.
Time frame: Up to 12 weeks
Change in global health status as measured by EORTC QLQ-C30
The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 100. Higher values indicate better outcomes for global health status and functional scales, lower values indicate better outcomes for symptom scales
Time frame: Up to 5 years
Change in CRC-related quality of life as measured by EORTC QLQ-CR29
The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire for Colorectal Cancer (EORTC QLQ-CR29) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 100. Higher values indicate better outcomes for functional scales, lower values indicate better outcomes for symptom scales.
Time frame: Up to 5 years
Change in bowel function as measured by CCBDS
The Colon Cancer Bowel Dysfunction Score (CCBDS) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 36. Lower values indicate better bowel function and less bowel dysfunction.
Time frame: Up to 5 years
Change in overall daily function and care needs as measured by EQ-5D-5L
The EuroQol-5 Dimension 5 Levels (EQ-5D-5L) score is a patient reported outcome measure with the following characteristics: Minimum value: Less than 0. Maximum value: 1. Higher values indicate better health-related quality of life.
Time frame: Up to 5 years
Change in fatigue as measured by FACIT-Fatigue
The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 52. Higher values indicate less fatigue and better outcomes.
Time frame: Up to 5 years
Change in fear of cancer recurrence as measured by FCRI-SF
The Fear of Cancer Recurrence Inventory - Short Form (FCRI-SF) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 36. Lower values indicate less fear of cancer recurrence.
Time frame: Up to 5 years
Change in post-operative recovery as measured by QoR-15
The Quality of Recovery 15 (QoR-15) is a patient reported outcome measure with the following characteristics: Minimum value: 0. Maximum value: 150. Higher values indicate better postoperative recovery.
Time frame: Up to 5 years
Change in physical activity as measured by NPAQ-Short
The Nordic Physical Activity Questionnaire Short Form (NPAQ-Short) is a patient reported outcome measure with two close-ended question items and categorical responses paired with two ad-hoc items. These assess self-reported hours spent on physical activity in a typical week as well as historic trends and interest in being more physically active.
Time frame: Up to 5 years
Change in physical fitness as measured by the 6-minute walk test
Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the 6-Minute Walk Test (6MWT)
Time frame: Up to 12 weeks
Change in physical fitness as measured by the sit-to-stand test
Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the Sit-to-Stand Test
Time frame: Up to 12 weeks
Change in physical fitness as measured by hand grip strength
Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in hand grip strength
Time frame: Up to 12 weeks
Change in physical fitness as measured by the Borg Rating of Perceived Exertion scale
Assessment of the efficacy of supervised exercise training during treatment, evaluated by changes in the Borg Rating of Perceived Exertion scale. Minimum value: 6. Maximal value: 20. Higher values indicate greater perceived effort and exercise intensity.
Time frame: Up to 12 weeks
Change in frailty as measured by the G8 frailty score
Assessment of the change in frailty after supervised exercise training, evaluated by changes in the G8 frailty score. Minimum value: 0. Maximum value: 17. Higher values indicate better outcomes for functional impairment.
Time frame: Up to 12 weeks
Compliance with supervised training program
Assessment of compliance with supervised training measured as the number of supervised training sessions attended during the intervention period
Time frame: Up to 12 weeks
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